Blood markers for the diagnosis and prognosis of stroke

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Abstract

Many blood markers have been associated with stroke. I set out to determine
whether blood markers can be applied to: (i) improve the accuracy of the clinical
diagnosis of stroke or TIA, and/or (ii) improve the prediction of poor outcome in
patients who are still symptomatic at the time of admission with stroke or TIA.
I systematically reviewed the existing literature on the diagnostic performance of a
range of blood markers measured soon after stroke onset, to inform the choice of
markers for my subsequent prospective studies in this thesis. Many studies had
deficiencies in their design, which may have explained the apparently – and
perhaps spuriously - impressive diagnostic performance of several markers. In the
light of these data I was able to improve the design of my own studies and suggest
how future studies of diagnostic markers could be improved.
In order to define an appropriate comparator test for assessing the diagnostic
accuracy of blood markers, I first examined the performance of emergency room
nurses and doctors. I assessed the accuracy of their diagnosis of TIA or stroke
(‘acute cerebrovascular disease’) in patients presenting with symptoms of suspected
stroke, and compared them with a number of stroke diagnostic scales. In the 405
patients recruited to the study, the sensitivity of emergency department staff was
77% and specificity 58%. Each stroke diagnostic scale had a slightly better
sensitivity, though worse specificity, than an emergency department clinician. I
decided to use the diagnosis by an emergency department clinician of ‘probable or
definite acute cerebrovascular disease’ as the best clinical performance reference
standard.
In blood taken from the same cohort of 405 patients, accredited research laboratories
measured markers of inflammation, thrombosis, thrombolysis, cardiac strain and
cerebral damage. Tissue plasminogen activator and loge N-terminal pro brain
natriuretic peptide were associated positively with a diagnosis of acute cerebrovascular disease, though each marker did not add diagnostic value to the
diagnosis of an emergency department doctor or nurse.
I systematically reviewed the literature examining the association between the levels
of blood markers with poor outcome (i.e. death or dependency) after stroke. I found
that although almost all markers studied had a positive association with poor
outcome, there were methodological problems with many studies, chiefly small
sample size, publication bias or within study reporting biases, and lack of
adjustment for important confounders such as age or stroke severity.
With data from the Edinburgh Stroke Study, I examined the association between
circulating markers of the inflammatory response (white cell count, interleukin-6, Creactive
protein and fibrinogen) and poor outcome after stroke. After adjustment for
age, whether the patient lived alone, was independent of activities of daily living,
was orientated, able to lift both arms and able to walk, I found that higher levels of
interleukin-6, white cell count and glucose were associated with poor outcome. The
relevant test of a biological marker is not its predictive ability alone, but whether,
when added to a validated predictive model based on clinical variables, it improves
the prediction of outcome. No individual marker improved the prediction of poor
outcome when added to a validated prognostic model based on clinical variables
alone.
From my cohort of 405 patients with suspected stroke 285 patients had a confirmed
diagnosis. Follow up of these 285 patients with confirmed acute cerebrovascular
disease showed that, after adjustment for neurological impairment and age, only
interleukin-6 and N-terminal pro brain natriuretic peptide were significantly
associated with death or disability at 3 months. Neither marker improved the
predictions of a model to predict poor outcome based on clinical variables alone.
To examine the relationship between circulating markers of the inflammatory
response and recurrent stroke, myocardial infarction, and vascular death (‘recurrent
vascular events’), again I used data from the Edinburgh Stroke Study. After adjustment for clinical predictors (age, prior MI, stroke, or TIA and AF) I found that
higher levels of interleukin-6, C-reactive protein and fibrinogen remained
significantly associated with an increased risk of recurrent vascular events.
However, the relationship with deaths from all causes was somewhat stronger for
each marker, perhaps suggesting that higher marker levels were associated with
debility rather than vascular events per se.
In conclusion, I found no marker measured could improve on the diagnostic
accuracy of an emergency department clinician for acute cerebrovascular disease,
nor improve the prediction of poor outcome by a prognostic model based upon
clinical variables. The work of this thesis does not support the routine use of blood
markers as an aid to the diagnosis of, or the prediction of outcome of, acute stroke.